Management of Relapsing-Remitting MS in a Changing Therapeutic Landscape - PowerPoint Presentation

1. Management of Relapsing-Remitting MS in a Changing Therapeutic LandscapeMichelle H. Cameron, MD, PT, MCR

2. Title and AffiliationMichelle H. Cameron, MD, PT, MCRAssociate ProfessorDepartment of NeurologyOregon Health & Science UniversityActing Chief of NeurologyVA Portland Health Care SystemCo-Director and Associate Director for ResearchVA MS Center of Excellence West

3. DisclosuresConsultant/Independent Contractor: Adamas Pharmaceuticals, Greenwich BiosciencesAdvisory Board: Helius Medical, inc.

4. Learning Objectives

5. OutlineClinical caseMS backgroundHistory of MS Disease Modifying Therapies – The “Old” DMTs, the “Newer” DMTsWhere we are today – The “Newest” DMTsHow to choose a DMT with our patients with RRMSWho is likely to benefit from an initially more aggressive therapy?

6. Clinical Case Date of visit: 8/2/20CC/ID: 25 yo male presents with recent episode of diplopia concerning for MSHPI: Diplopia onset 6/8/20, worst looking down and to the right, now almost fully resolved. MRI brain showed ~ 1 dozen T2 hyperintense lesions, supra and infratentorial, 2 enhancing.

7. HistoryAbout 1 month of right facial numbness in 2019About 1 month of bilateral hand numbness in 2017

8. ExamWNL except for bilateral brachioradialis hyperreflexia

9. Diagnosis of MSClinical historyMRI brainOther supportive testingMRI spineCSFVEEP

10. MRI brain 6/10/10FLAIR (fluid attenuation inversion recovery)

11. MRI brain 6/10/10: T1 contrast

12. MSMultiple scars in the CNS, optic nervesNeurological symptoms separated in time and spaceNo better explanation

13. Course of MSTypes of MSRelapsing remitting (~85% at onset)Secondary progressive (~50% of RRMS at 10-15 years from onset)Primary progressive (~ 15% at onset)

14. Who gets MSF>M, 2-4:1Young adult onset, lifelong diseaseBeyond the 40° latitude (Portland is 45°)Genetic predisposition

15. Treatment/ManagementDisease modifying therapies (>20)Reduce relapse rateSlow accumulation of disabilityApproved for relapsing forms of MS Clinically isolated syndrome, Relapsing-remitting disease, Active (with relapses or new MRI activity) secondary progressive diseaseNONE approved for inactive secondary progressive MS1 approved for PPMS (Ocrelizumab)Relapse management – high dose steroidsSymptom management

16. DMT history, the “old” DMTs – pre 2010DMTApprovalLikely MOARouteConsiderationsInterferon Beta1993 - 2014Reduced T cell activation/proliferation, secretion of MMPs, expression of HLA, inhibit IFN gammaInjectionLeukocytopenia, increased LFTs, flu-like symtoms, ? Depression, modest efficacy ~↓ARR ~30%Glatiramer Acetate1996 - 2014Th1 to Th2 shift; block MHC peptide antigenInjectionInjection site lipoatrophy, high safety and tolerability, modest efficacy ~↓ARR ~25%3 generics now available (2015, 2017, 2018)Natalizumab2004Binds Alpha-4 integrin on immune cells preventing interaction with vascular endothelium and transmigration to CNSInfusionPML (~ 1/250), high efficacy ~↓ARR 60-70%

17. DMT history, the “middle” DMTs –2010 - 2015DMTApprovalLikely MOARouteConsiderationsFingolimod 2010Sphingosine 1-phosphate receptor modulator; prevents activated lymphocyte egress from secondary lymphoid organs to circulationOralFirst dose bradycardia.HTN, macular edema, increased LFTs, lymphopenia, ocular melanoma (PML total ~ 15), fairly high efficacy ~↓ARR 50%Teriflunomide 2012Inhibits dihydro-orotate dehydrogenase; decreases proliferation of activated immune cellsOralHair loss, teratogenicity (men and women), “category X”, screen for TB, modest efficacy ~↓ARR ~25%Dimethyl fumarate2013Th1 to Th2 shift; activates NrF2 transcriptionOralEarly GI sx, flushing, lymphopenia (PML total ~ 10 with MS), fairly high efficacy ~↓ARR 50%Alemtuzumab2014Antibody-dependent cell-mediated lysis following binding of drug to CD52 antigen present on immune cellsInfusionInfusion reactions, autoimmune thyroid disease in ~ 25%, ITP in ~1-3%, Goodpasture’s syndrome in ~1%, high efficacy ~↓ARR 70%

18. DMTApprovalLikely MOARouteConsiderationsDaclizumab2016Targets CD25, prevents T cell activationInjectionWithdrawn 2018Ocrelizumab2017Anti-CD20, targets B cellsInfusionIV Q6 months, approved for PPMS, high efficacy ~↓ARR 70%Cladribine2019Interfere with DNA synthesis and repair in B and T cellsOralShort course 1x/year, lymphopenia,infection, incr LFTs, black box warning for malignancy, fairly high efficacy ~↓ARR 50%Siponimod2019Sphingosine 1-phosphate receptor modulatorOralGenotype sequencing CYP2C9 for dosing, titration but no first dose observationDiroximel fumarate2019Th1 to Th2 shift; activates NrF2 transcriptionOralBioequivalent to DMF but with less GI side effects, $88kThe “new” DMTs – approved 2015-2019

19. DMTApprovalLikely MOARouteConsiderationsMonomethyl fumarate2020Th1 to Th2 shift; activates NrF2 transcriptionOralActive metabolite of dimethyl and diroximel fumarateOzanimod2020Sphingosine 1-phosphate receptor modulatorOralInteraction w/ foods w/ high tyramine and MOAi (SSRI, SNRI), titration but no first dose observation or genetic testingOfatumumab2020Anti-CD20, targets B cellsInjectionSQ, monthly at home, fairly high efficacy ~↓ARR 50%The “newest” DMTs – approved so far in 2020

20. Soon to come?SQ rituximab for MSS1PR modulators – Ponesimod, AmiselimodLipoic acidTyrosine kinase inhibitors – Evobrutinib, MasitinibStem cell therapy (HSCT) (BEAT MS)Discontinuation trial ongoing (DISCO MS)

21. Choosing a DMT with our patients with RRMSBy route of administrationInjectableOralIVBy “benefit”By “risk”

22. Route of administration: Impacts adherence and monitoringInjectableRarely the patient’s preferred routeHave a long history of safety that may be preferredNo reason to change legacy patients who are doing wellGlatiramer probably has the best pregnancy safetyOralThe easiestBut there are often challenges with adherence, adherence monitoring and safety monitoringA misperception that easy = safeInfusion/IVAdds another costTakes coordinationTravel considerationsEasy to monitor adherence and check labs with infusions

23. Benefit – high efficacy vs low efficacyRange from ~ 25% to 70%+ ↓ ARRWhat does your patient need?What does your patient want?At what risk?

24. Risk – high risk vs low riskProbability – range of PML risk with natalizumab and othersSeverity – Herpes zoster vs PML vs malignancyTiming – early flu-like side effects with IFNs, early GI sx with DMF vs long term PML risk with natalizumabRisk vs tolerability – PML, malignancy, infection Vs. GI sx, flushingPrevention/risk reduction e.g. JCV Ab testing for PML, Hepatitis B testing before ocrelizumab, CBC with diff and LFT monitoring Treatable? e.g. thyroid dysfunction, herpes zoster, malignancy, PML, UTI, URI

25. What about the cost?1993 - ~$10k/year2004 average price $16k/year2013 average price $61k/year2017 average price $83k/year (even generics are > $60k/year)2019 median price $88k/year2020 …40% of people with MS alter or stop taking medications due to high cost (NMSS)11% could easily afford the cost of their medication without financial assistance

26. Who is likely to benefit from an initially more aggressive therapy?Early predictors of more aggressive diseaseAt diagnosisBowel and bladder symptoms at disease onsetMale sexOlder age at onsetMore lesions, more Gd+ lesionsOver the first few yearsPersistent disease activity on less aggressive therapyHigher relapse ratePoorer recovery from relapsesGd enhancing lesionsNew T2 lesions

27. ConclusionsThese are exciting times in MS care20+ DMTs and more all the timeThese are complex times in MS care20+ DMTs and more all the timeDifferent benefits and risks“Me too” drugsCostDecision whether to take a DMT, and if so which DMT, are made collaboratively and evolve over timeThe future is bright

28. ReferencesBrandstadter R, Katz Sand I. The use of natalizumab for multiple sclerosis. Neuropsychiatr Dis Treat. 2017;13:1691-1702. Confavreux C, O'Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247-256. Confavreux C, Vukusic S, Adeleine P, Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process, Brain. 2003;126(4):770–782.Davda N, Tallantyre E, Robertson NP. Early MRI predictors of prognosis in multiple sclerosis. J Neurol. 2019;266(12):3171-3173. Gajofatto A, Turatti M, Monaco S, Benedetti MD. Clinical efficacy, safety, and tolerability of fingolimod for the treatment of relapsing-remitting multiple sclerosis. Drug Healthc Patient Saf. 2015;7:157-167. Guarnera C, Bramanti P, Mazzon E. Alemtuzumab: a review of efficacy and risks in the treatment of relapsing remitting multiple sclerosis. Ther Clin Risk Manag. 2017;13:871-879. Hartung DM, Bourdette DN, Ahmed SM, Whitham RH. The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail? Neurology. 2015;84(21):2185-2192.Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286. Naismith RT, Wolinsky JS, Wundes A, et al. Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study [published online ahead of print, 2019 Nov 4]. Mult Scler. 2019;1352458519881761. Simone IL, Carrara D, Tortorella C, et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology. 2002;59(12):1922-1928. Viglietta V, Miller D, Bar-Or A, et al. Efficacy of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis: integrated analysis of the phase 3 trials. Ann Clin Transl Neurol. 2015;2(2):103-118.

29. Thank YouQ & A